Paroxetine

Indications

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), and, as such, is identified as an antidepressant. It is FDA approved for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), social anxiety disorder (SAD), panic disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and premenstrual dysphoric disorder (PMDD), vasomotor symptoms associated with menopause. [1] Paroxetine is not FDA approved for use in children and adolescents less than 18 years of age, however, it is still used off-label.

Off-Label Use

Obsessive-compulsive disorder (in children and adolescents)

Social anxiety disorder (in children and adolescents)

Separation anxiety

Dysthymia

Body Dysmorphic disorder

Postpartum Depression

Premature ejaculation

Malignancy related pruritus unresponsive to standard treatment

Mechanism of Action

Identified as an SSRI, paroxetine's signature mechanism of action is to block the serotonin reuptake transporter (SERT) and thus increase the concentration of synaptic serotonin. Current theory suggests that the diminished serotonin concentration in the depressed brain induces the upregulation of serotonergic receptors. By increasing the synaptic serotonin concentration, paroxetine thus induces the downregulation of the previously upregulated serotonin receptors, thus normalizing the receptor concentration. [2] Furthermore, in a radioligand study, paroxetine showed some affinity for muscarinic, adrenergic (alpha and beta), dopaminergic (D2), serotonergic (5-HT2), and histaminergic (H1) receptors.[3] These receptors have also been thought to contribute to its antidepressant effects, as well as its side effect profile.

Administration

Paroxetine is administered orally. The medication should be titrated based on the patient's symptoms and tolerance to dosage. The drug can be taken with or without food. In addition to regular tablets, it is available in a controlled-release tablet, as well as liquid form. Paroxetine may be administered at any time of the day, depending on toleration.

Metabolism

The steady-state mean values of T1/2 is 21 hours. Paroxetine is metabolized by hepatic CYPP450 2D6. 2% is excreted by the urine, 62% metabolized over a 10-day post-dosing period, 36% excreted in the feces. Paroxetine inhibits CYP2D6 and, thus, its own metabolism; plasma concentrations can potentially double following dosage increases of 50%. [4]

In hepatic impairment that plasma concertation is two times that is seen in normal function.

If mild to moderate: no change in dosage

If severe

Immediate-release formulations: 10 mg per day and if needed increase by 10 mg per day at intervals of 1 week; maximum dose of 40 mg per day

Controlled release formulation: 12.5 mg per day; increase if needed by 12.5 mg per day increments at intervals of 1 week; Maximum dose of 50 mg per day

Adverse Effects

Many of the side effects of paroxetine are dose-dependent. Side effects that are most common include drowsiness, dry mouth, loss of appetite, sweating, sleep disturbance, and sexual side effects (sexual side effects can best be augmented with prescription of medications like sildenafil). Discontinuation syndrome is more common and more severe with paroxetine than with other SSRIs; this may be due in part to the fact that it inhibits its own metabolism. Withdrawal symptoms from discontinuation include dizziness, lethargy, nausea, vomiting, headache, fever, chills, vivid dreams, electric shock-like-sensation, dyskinesia, anxiety, crying, irritability, and depersonalization. [5]

Other Adverse Effects

Psychiatric: Apathy and emotional flattening (indirect decrease of dopamine), hypomania or mania (1%). In children and adolescents and young adults (18-24 years of age) paroxetine increase the risk of suicide

induction of agitation or manic state may be representative of an underlying bipolar condition that requires the addition of a mood stabilizer, lithium, an atypical antipsychotic, and/or the discontinuation of paroxetine

Contraindications

There are only a few absolute contraindications for the use of paroxetine. Absolute contraindications include concurrent use of monoamine oxidase inhibitors (MAOIs), thioridazine, and pimozide. Concurrent use of MAOIs and paroxetine can precipitate serotonin syndrome. Concurrent use of thioridazine and paroxetine can induce cardiac arrhythmias; similar effects are observed with pimozide and paroxetine. [6]

Paroxetine is not recommended for use during pregnancy or if breastfeeding. Based on epidemiological studies, infants exposed to paroxetine during the first trimester had an increased risk for cardiovascular malformations. [6]

Monitoring

Patients initiated on paroxetine should be observed closely, initially, and monitored for worsening clinical symptoms, behavior changes (mania, social function, anxiety) or suicidal ideations. Labs should include serum sodium concentration to rule out SIADH. [7] Vital signs should be monitored for signs of serotonergic hyperactivity. Serotonin syndrome precipitates via the manifestation of changes in mental status, autonomic instability, gastrointestinal symptoms, hyperreflexia, and myoclonus. Serotonin syndrome can be treated by discontinuing any of the offending agents. If symptoms continue to escalate, the clinician can administer cyproheptadine. [8]

Toxicity

Though it is rarely lethal in overdose by itself, patients can develop somnolence, nausea, tremor, heart rhythm disturbances, confusion, vomiting, dizziness, and mydriasis. During toxicity, a patient’s airway, oxygenation, and ventilation should be assessed first. The treatment for overdose includes symptomatic supportive treatment. There is no specific treatment for paroxetine toxicity.[9]

Enhancing Healthcare Team Outcomes

Interprofessional teamwork can impact a patient's outcome positively. The increase in communication between the various department such as pharmacy and psychiatry can overall benefit the patient.[10] Each department acknowledges what the patients' needs and implement the plan. The pharmacist can provide the dosing for the patient and monitor toxicity levels and consult with the prescriber for changes. Each patient is unique; some may require a different dosage because of renal of hepatic dysfunction. This allows the patient to have a correct dosage based on their co-morbid conditions. Nursing should be alert to signs of adverse drug events, improvement in status, or the need for further evaluation, and report such to the clinician. The psychiatrist can also monitor the patient clinically for improvement, or if needed, make changes in the medication. This interprofessional paradigm can improve patient outcomes through enhanced treatment strategies and information sharing. [Level 5]